Warfarin is the most widely prescribed oral anticoagulant for the treatment and prevention of thromboembolic diseases. The high inter-individual variability in warfarin dosing is an ongoing problem that is worsening as the population ages and eligible patients increase in numbers. Effectiveness and safety of warfarin therapy are routinely monitored by the international normalized ratio (INR), the ratio of time required for coagulation relative to a reference. More particularly, the international normalized ratio (INR) is a system for reporting the results of blood coagulation tests. For example, a person taking the anticoagulant warfarin might optimally maintain a prothrombin time of 2 to 3 INR. No matter what laboratory checks the prothrombin time, the result should be the same even if different thromboplastins and instruments are used. The international normalized ratio (INR) standardization permits patients on warfarin to obtain comparable test results at different locations.
Despite the large number of anticoagulation clinics and efficient INR monitoring programs, up to 15% of warfarin users suffer from bleeding and 11% from thromboembolic events that can lead to hospitalizations and deaths. INR fluctuations above the targeted therapeutic INR range in particular are associated with an accrued risk of bleeding. For every unit increase in INR, one study reported an increase in odds of major bleeding by 0.6 in younger patients and by 0.4 in older patients. In a hospital-based study, INR values ≧4 were shown to be associated with a marked increase in bleeding risk (OR 13, 95% CI 1.2-150). Still, patients fluctuate above their target therapeutic INR range in as high as 30% of the time in the first 3 months of treatment, and 14% subsequently.
The relative contribution of different polymorphisms to warfarin dosing has already been studied in various patient populations and ethnic comparisons have been made. Most previous studies have focused on the use of genetic polymorphisms to predict stable therapeutic dose, the impact of the algorithm on the percentage of patients who are outside of the therapeutic range or the time to stable INR and warfarin dose. A question of immediate clinical relevance, however, is whether a patient's genetic information can be used to reduce the occurrence of serious clinical events due to warfarin treatment.
Against this background, there exists a need for a new and improved methods for reducing the occurrence of serious clinical events due to warfarin treatment.